Resistance to anticancer drugs represents a major obstacle to successful cancer treatment. Various resistance mechanisms and alternate survival pathways have been described (Redmond et al., Front Biosci 13:5138-5154, 2008). Recent findings have revealed non-mutational mechanisms of drug resistance. Trumpp and Wiesletler (Nat Clin Prac Oncol 5, 337-347, 2008) described a small population of “cancer stem cells” that are intrinsically more refractory to the effects of a variety of anticancer drugs, possibly via enhanced drug efflux. Other studies have implicated epigenetic mechanisms, suggesting that acquired drug resistance does not necessarily require a stable heritable genetic alteration (Glasspool et al., Br J Cancer, 94:1087-1092, 2006). It was demonstrated in non-small cell lung cancer (NSCLC) patients, who responded well to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and who later experienced therapy failure, but demonstrated a second response to EGFR TKI re-treatment after a “drug holiday” (Kurata et al., Ann Oncol 15:173-174, 2004; Yano et al., Oncol Res 15:107-111, 2005). Similar re-treatment responses are well established for several other anticancer drugs (Cara & Tannock, Ann Oncol 12:23-37, 2001). These findings suggest that acquired resistance to cancer drugs involves a reversible “drug-tolerant” state.
Recent data point to the pre-existence of a subpopulation of cancer cells termed drug-tolerant persisters (DTPs) that exhibit an epigenetically-mediated tolerance to high concentrations of chemotherapeutic drugs (Sharma et al., Cell 141:69-80, 2010). Although DTPs are largely quiescent, a small fraction of these cells resumes growth even in the presence of 100×IC50 drug concentrations, giving rise to drug-tolerant expanded persisters (DTEPs). Levels of histone H3 lysine 4 (H3K4) methylation and H3K14 acetylation are significantly decreased in DTPs and DTEPs.
As resistance to anticancer drugs remains a major challenge in anticancer therapy, there is a need for compounds capable to overcome this resistance.